Research

JAMA Ophthalmology | Original Investigation

Association of Repeated Intravitreous Bevacizumab Injections

With Risk for Glaucoma Surgery
Brennan D. Eadie, MD, PhD; Mahyar Etminan, PharmD, MSc; Bruce C. Carleton, PharmD;
David A. Maberley, MD, FRCSC; Frederick S. Mikelberg, MD, FRCSC

Invited Commentary
IMPORTANCE Intravitreous injections of anti–vascular endothelial growth factor (VEGF) page 368
agents are associated with a sustained increase in intraocular pressure. This sustained Supplemental content
elevated intraocular pressure could lead to higher rates of glaucoma surgery to lower this
pressure.

OBJECTIVE To determine the risk of glaucoma surgery following repeated intravitreous

bevacizumab injections.

DESIGN, SETTING, PARTICIPANTS This nested, case-control study acquired and analyzed data
from large, population-based, linked health databases supported by the British Columbia
Ministry of Health in Canada. Study participants included all patients with ophthalmic issues
in British Columbia, such as those of the Provincial Retinal Diseases Treatment Program, who
had received intravitreous bevacizumab injections for exudative age-related macular
degeneration between January 1, 2009, and December 31, 2013. Cases were identified using
glaucoma surgical codes for trabeculectomy, complicated trabeculectomy, glaucoma drainage
device, and cycloablative procedure. For each case, 10 controls were identified and matched
for age, preexisting glaucoma, calendar time, and follow-up time. The number of intravitreous
bevacizumab injections received per year—3 or fewer, 4 to 6, or 7 or more—was determined
for both cases and controls. Data analysis was performed from February 23, 2016, to
November 14, 2016.

MAIN OUTCOMES AND MEASURES Risk of glaucoma surgery compared with the number of
intravitreous bevacizumab injections per year in cases and controls. Rate ratios were adjusted
for covariates (diabetes mellitus, myocardial infarction, stroke, and verteporfin use).

RESULTS Seventy-four cases of glaucoma surgery and 740 controls were identified, with a
mean (SD) age of 81.3 (8.4) years for cases and 81.4 (7.9) for controls. The case group had
more males than the control group (38 [51.4%] vs 272 [36.8%]). The adjusted rate ratio of
Author Affiliations: Department of
glaucoma surgery among those who received 7 or more injections per year was 2.48 (95% CI, Ophthalmology and Visual Sciences,
1.25-4.93). There was a 10.3% higher number of 7 or more injections among cases compared Faculty of Medicine, University of
with controls. The adjusted rate ratio for those who received 4 to 6 injections per year British Columbia, Vancouver, British
Columbia, Canada (Eadie, Etminan,
compared with those who received 3 or fewer was 1.65% (95% CI, 0.84-3.23). Maberley, Mikelberg); Division of
Translational Therapeutics,
CONCLUSIONS AND RELEVANCE Findings from this large, pharmacoepidemiologic study Department of Pediatrics, Faculty of
Medicine, University of British
suggest that 7 or more intravitreous injections of bevacizumab annually is associated with a
Columbia, Vancouver, British
higher risk of glaucoma surgery and that 4 to 6 injections per year show a nonstatistically Columbia, Canada (Carleton); Child
significant rate ratio in the same direction. and Family Research Institute,
University of British Columbia,
Vancouver, British Columbia, Canada
(Carleton); Pharmaceutical Outcomes
Programme, British Columbia
Children’s Hospital, Vancouver,
British Columbia, Canada (Carleton).
Corresponding Author: Mahyar
Etminan, PharmD, MSc, Department
of Ophthalmology and Visual
Sciences, Faculty of Medicine,
University of British Columbia,
Room 323-2550 Willow St,
JAMA Ophthalmol. 2017;135(4):363-368. doi:10.1001/jamaophthalmol.2017.0059 Vancouver, BC V5Z 3N9, Canada
Published online March 16, 2017. (etminanm@mail.ubc.ca).

(Reprinted) 363

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 Research Original Investigation
T
he advent of intravitreous anti–vascular endothelial
growth factor (VEGF) injections to treat common causes
of vision loss, such as exudative age-related macular de-
generation (AMD),1-3 diabetic macular edema,4-6 and edema
associated with retinal vein occlusion,7-10 has undoubtedly im-
proved visual outcomes for many patients. Major prospec-
tive clinical trials investigating variable dosing regimens of in-
travitreous anti-VEGF injections for exudative AMD have
revealed that some patients may require monthly injections
during the first 1 to 2 years of treatment and that, on average,
10 injections are required in the first 2 years of treatment.11,12
Minimal adverse events were reported in those trials and some
conflicting results exist, but subsequent studies suggest that
repeated intravitreous anti-VEGF injections can lead to a sus-
tained increase in intraocular pressure (IOP).13-22
In 2007, Jalil and colleagues13 reported a case of ocular hy-
pertension with a marked rise in IOP 3 days after the patient’s
fourth monthly intravitreous injection of bevacizumab for exu-
dative AMD. In 2008, Bakri and colleagues14 reported a case
series of 4 nonglaucomatous patients receiving intravitreous
ranibizumab who developed a sustained increase in IOP. Simi-
lar studies have been published since those initial case series,
including research suggesting that intravitreous bevaci-
zumab injections cause sustained increases in IOP.15,16 Retro-
spective chart reviews support this association, reporting that
approximately 6% to 9% of patients receiving intravitreous
anti-VEGF injections experienced sustained IOP elevation.17-19
A similar value was observed in an exploratory analysis of the
Diabetic Retinopathy Clinical Research Network randomized
clinical trial.20 Many of those studies suggest that the risk of
sustained IOP rise is positively associated with the number of
injections that the patient has received.16,17,21 To date, there
has not been a large epidemiologic study that has investi-
gated the risk of a clear glaucoma outcome (ie, less prone to
bias using a retrospective health database analysis), such as
glaucoma surgery, following repeated intravitreous anti-
VEGF injections.
Intravitreous injections of anti-VEGF agents may in-
crease the risk of increased IOP13-22; however, the risk of de-
veloping moderate to advanced glaucoma requiring glau-
coma surgery has been unclear. A single, small case series
suggests that at least some patients with or without glau-
coma at baseline may go on to require a trabeculectomy.22
Therefore, using large, population-based linked health data-
bases, we conducted a pharmacoepidemiologic, nested, case-
control study to examine the possible association of repeated
intravitreous bevacizumab injections with subsequent glau-
coma surgery.
Methods
Setting and Patient Population
This population-based, observational study used the linked da-
tabases supported by the British Columbia Ministry of Health.
In British Columbia, Canada, patients with retinal diseases are
entitled to receive anti-VEGF medication through the Provin-
cial Retinal Diseases Treatment Program. The program records
364 JAMA Ophthalmology April 2017 Volume 135, Number 4 (Reprinted)
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Repeated Bevacizumab Injections and Risk for Glaucoma Surgery
Key Points
Question Do repeated intravitreous bevacizumab injections
increase the risk for glaucoma surgery?
Finding In this case-control study of 74 patients who underwent
glaucoma surgery and 740 control participants, the adjusted rate
ratio for glaucoma surgery was higher for patients who received 7
or more intravitreous bevacizumab injections per year than for
those who received 3 or fewer intravitreous bevacizumab
injections per year.
Meaning Patients who receive 7 or more intravitreous
bevacizumab injections per year have an increased risk of requiring
glaucoma surgery.
clinical ophthalmic data for all patients, including intravitre-
ous anti-VEGF injections, in a comprehensive database that is
subject to frequent quality control and is linkable to other
Ministry of Health–supported databases. These databases have
been used in many previous epidemiologic studies23-25 and in-
clude the Discharge Abstract Database,26 which captures all
hospitalizations; the Medical Services Plan database,27 which
contains all physician visits; and the Medical Services Plan pre-
scription drugs database, which records all medications dis-
pensed to patients.28 Data analysis was performed from Feb-
ruary 23, 2016, to November 14, 2016. Ethics approval for this
study was granted before commencement by the University of
British Columbia’s Clinical Research Ethics Board, and the study
design and execution adhered to the tenets of the Declaration
of Helsinki.29 Patient informed consent was waived by the
University of British Columbia’s Clinical Research Ethics Board
because individual patients are anonymized in the databases.
Cohort and Case-Control Analysis
The cohort comprised patients who received their first intra-
vitreous bevacizumab injection for exudative AMD between
January 1, 2009, and December 31, 2013. Cases were defined as
patients in the cohort who subsequently underwent glaucoma
surgery. The date of glaucoma surgery was the index date. For
each case, 10 controls (no surgical procedure code at any time
of follow-up) were selected and matched by age, preexisting
glaucoma, number of injections per year, calendar time, and fol-
low-up time (matching protocol below). Glaucoma surgery cases
were identified using these surgical procedural codes, which are
part of the payment schedule created by the Medical Services
Commission to reimburse services clinicians provide to ben-
eficiaries of the Medical Services Plan: trabeculectomy (02187),
complicated trabeculectomy (22187), glaucoma drainage de-
vice (22070), and cycloablative procedure (22185).
Calendar time and follow-up time matching was achieved
by selecting controls who received their first bevacizumab in-
jection in the same year and had the same duration of
follow-up as the cases between injection and date of glau-
coma surgery (index date). Calendar time matching de-
creases the likelihood that trends for a particular procedure that
differ by calendar year (eg, introduction of new guidelines for
a specific procedure) will affect cases and controls dispropor-
tionately. Matching by follow-up time balances between cases
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 Repeated Bevacizumab Injections and Risk for Glaucoma Surgery Original Investigation Research

and controls the opportunity to undergo glaucoma surgery,

Table 1. Characteristics of Glaucoma Surgery Cases and Controls
controlling for time window bias.25 Cases and controls were
matched for preexisting glaucoma to control for the in- Cases Controls
Characteristic (n = 74) (n = 740)
creased probability of glaucoma surgery in patients with pre- Age, mean (SD), y 81.3 (8.4) 81.4 (7.9)
existing glaucoma. Follow-up, mean (SD), y 1.5 (0.9) 1.5 (0.9)
The exposure investigated was the frequency of intravit-
Male, No. (%) 38 (51.4) 272 (36.8)
reous bevacizumab injections in cases and controls. Thresh-
Comorbidities, No. (%)
olds of the number of injections received per year were 3 or
Glaucoma 58 (78.4) 429 (78.4)
fewer, 4 to 6, or 7 or more; these cutoffs were chosen to en-
Diabetes 9 (12.2) 67 (7.6)
sure a robust sample size in the reference category. Data were
Myocardial infarction 2 (2.7) 15 (3.7)
analyzed in the same manner but with the total number of in-
Stroke 0 6 (0.8)
travitreous bevacizumab injections as the exposure and the
Verteporfin use 2 (2.5) 14 (2.1)
thresholds as 6 or fewer, 7 to 11, or 12 or more (eTable in the
Supplement).
Table 2. Crude and Adjusted Rate Ratios for Glaucoma Surgery
and Number of Intravitreous Bevacizumab Injections per Year
Intravitreous Anti-VEGF Injections
Bevacizumab is the anti-VEGF medication provided by the Injections Rate Ratio (95% CI)
per Year, Cases Controls
Provincial Retinal Diseases Treatment Program to most pa- No. (%) (n = 74)a (n = 740)b Crude Adjustedc
tients in British Columbia with exudative AMD. In this study, ≤3 18 (24.3) 255 (34.5) 1 [Reference] 1 [Reference]
bevacizumab was also the anti-VEGF medication used for all 4-6 23 (31.1) 231 (31.2) 1.42 1.65 (0.84-3.23)
patients in the cohort. A licensed pharmacist at a compound- ≥7 33 (44.6) 254 (34.3) 2.02 2.48 (1.25-4.93)
ing pharmacy, approved by the College of Pharmacists of a
Cases were defined as individuals identified by glaucoma surgery.
British Columbia and the Provincial Retinal Diseases b
Controls were matched for age, preexisting glaucoma, cohort entry date, and
Treatment Program, compounds and dispenses bevaci- duration of follow-up.
zumab. Commercially available vials of the anti-VEGF medi- c
Rate ratios were adjusted for the variables in Table 1.
cation, which is supplied by the Ministry of Health, are used
to fill ultrafine diabetic syringes (BD ultrafine II ½ CC age and preexisting glaucoma. The mean (SD) age was 81.3 (8.4)
syringes; BD Worldwide) containing 0.05 mL of the drug. The years for cases and was 81.4 (7.9) years for controls (Table 1).
syringes are then transported and stored at 4°C until used by There were more males in the case group (38 [51.4%]) than in
the vitreoretinal specialist. the control group (272 [36.8%]). The frequency of the poten-
tial confounding variables (ie, diabetes, myocardial infarc-
Statistical Analysis tion, stroke, and verteporfin use) was not different between
The demographics of cases and controls were examined using the 2 groups.
descriptive statistics. For the case-control analysis, patients The percentage of cases identified who received 7 or more
who received 3 or fewer injections per year (or ≤6 total injec- intravitreous bevacizumab injections per year (44.6% [n = 33])
tions in the supplementary analysis) served as the reference was greater than the percentage of controls who received 7 or
category. Controls were allowed to become future cases (ie, ex- more intravitreous bevacizumab injections per year (34.3%
perience a future surgical procedure), allowing the odds ratio [n = 254]) (absolute increase, 10.3%; Table 2). Compared with
to closely approximate a rate ratio (RR) derived from a cohort the reference group (ie, those who received ≤3 intravitreous
study.30 Crude and adjusted RRs were approximated from a bevacizumab injections per year), an increased RR was ob-
conditional logistic regression model. The RRs were adjusted served for cases vs controls who received 7 or more intravit-
for the following covariates: diabetes, myocardial infarction, reous bevacizumab injections per year (adjusted RR, 2.48;
stroke, and verteporfin use (Visudyne; Novartis and QLT 95% CI, 1.25-4.93). Compared with the reference group, there
PhotoTherapeutics). To avoid indiscriminant adjustment of was no difference in the RR for cases vs controls who re-
covariates that may lead to overadjustment bias, causal dia- ceived 4 to 6 intravitreous bevacizumab injections per year (ad-
grams of potential confounding variables were used to iden- justed RR, 1.65; 95% CI, 0.84-3.23). These data show that re-
tify true confounding variables (ie, variables that appear to be ceipt of 7 or more, but not 4 to 6, intravitreous bevacizumab
associated with exposure and outcome) and adjustment of injections per year is associated with an increased risk of sub-
covariates at baseline.31,32 sequent glaucoma surgery. Similar results were obtained when
the total number of injections were used as the exposure group
(eTable in the Supplement).

Results
We identified the cases of 75 patients who had received intra-
vitreous bevacizumab injections for exudative AMD. One pa-
Discussion
tient also had a central retinal vein occlusion and was ex- Several case reports, retrospective studies, and post hoc ex-
cluded from the study, leaving 74 cases for analysis. We ploratory analyses of prospective clinical trials13-22 have asso-
identified 740 corresponding controls who were matched for ciated intravitreous injections of anti-VEGF agents with a sus-

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 Research Original Investigation
tained increase in IOP. Some of those studies suggest that the
elevation in IOP becomes apparent only after repeated injec-
tions of anti-VEGF agents.16,17,19,21 In our study, we used large
linked databases supported by the British Columbia Ministry
of Health to examine the possible association of repeated in-
travitreous bevacizumab injections with glaucoma surgery. We
observed an adjusted RR of 2.48 (95% CI, 1.25-4.93) for glau-
coma surgery in patients who received 7 or more intravitre-
ous bevacizumab injections per year. These data suggest that
repeated intravitreous anti-VEGF injections could lead to a rise
in IOP-lowering surgical procedures for glaucoma and a sus-
tained increase in IOP.
The mechanism by which repeated intravitreous anti-
VEGF injections may lead to sustained IOP elevation is not clear.
Many hypotheses have been offered, including trabecular
meshwork injury from rapid injections of high volumes of
fluid,33 altered nitric oxide metabolism in the trabecular
meshwork,34 a potentially toxic or inflammatory reaction af-
ter exposure to the biologic agent and/or vehicle, and mechani-
cal blockade of the trabecular meshwork by protein aggre-
gates or contaminant particles associated with packaging and
injection techniques.35 Although our data do not help clarify
the pathogenesis of this observation, they do suggest that the
mechanism can be substantial enough to cause glaucoma that
requires surgical intervention.
An important finding in this study is the increased risk of
glaucoma surgery associated with 7 or more intravitreous in-
jections of bevacizumab per year. This finding corroborates those
of many studies that use sustained increased IOP as the out-
come measure after repeated intravitreous anti-VEGF
injections.16,17,19,21 Clinical trials investigating the efficacy of anti-
VEGF in treating exudative AMD, such as MARINA
(Minimally Classic/Occult Trial of the Anti-VEGF Antibody
Ranibizumab in the Treatment of Neovascular Age-Related
Macular Degeneration) and ANCHOR (Anti-VEGF Antibody for
the Treatment of Predominantly Classic Choroidal Neovascu-
larization of Age-Related Macular Degeneration), did not re-
port a significant long-term effect of ranibizumab on IOP. How-
ever, a post hoc analysis of MARINA and ANCHOR did
demonstrate that eyes treated with ranibizumab were more
likely to have an IOP increase greater than 6 mm Hg and a pre-
injection IOP greater than 24 mm Hg on at least 2 consecutive
visits.1-3 This post hoc analysis did not reveal statistically sig-
nificant differences in glaucoma-related end points, such as use
of IOP-lowering medications, laser trabeculoplasty, peripheral
iridotomy, or trabeculectomy. Many differences exist between
our study and the MARINA and ANCHOR trials, including the
study design, use of ranibizumab in MARINA and ANCHOR,
shorter duration of follow-up in MARINA and ANCHOR, and con-
trol group receiving sham injection, photodynamic therapy, and
possibly steroid injections in MARINA and ANCHOR. Simi-
larly, a separate ad hoc, exploratory analysis conducted by the
Diabetic Retinopathy Clinical Research Network reported sus-
tained IOP elevation with repeated ranibizumab injections for
diabetic macular edema, suggesting that this effect is likely not
limited to patients with exudative AMD.20
The present study was restricted to use of the VEGF in-
hibitor bevacizumab because this medication is supported by
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Repeated Bevacizumab Injections and Risk for Glaucoma Surgery
the Provincial Retinal Diseases Treatment Program and is
widely used by most of its patients. Previous studies suggest
that the putative effect of intravitreous anti-VEGF injections
on IOP, and possibly on glaucoma, may not be produced by be-
vacizumab alone. Case studies have suggested that the
effect of intravitreous anti-VEGF medications on sustained
increased IOP is the result of both bevacizumab and
ranibizumab.13-16,19 In a retrospective review by Choi and
colleagues,18 sustained IOP elevation occurred after intravit-
reous injections of bevacizumab, ranibizumab, or pegap-
tanib sodium. In the case series by Skalicky and colleagues,22
all patients who went on to require a trabeculectomy had re-
ceived ranibizumab. Larger studies are required to clarify
any potential differences in effects of repeated intravitreous
injections of different anti-VEGF agents on the need for
glaucoma surgery.
Strengths and Limitations
Our study has many important strengths. First, its large
sample size allowed for appropriate quantification of the
relationship between the frequency (and total number; see
eTable in the Supplement) of repeated intravitreous bevaci-
zumab injections and surgical intervention for glaucoma. The
use of glaucoma surgery as a hard outcome is a novel
approach to addressing the potential association between
glaucoma and intravitreous bevacizumab injections; previ-
ous large studies were limited to associations between
repeated intravitreous anti-VEGF injections and sustained
increases in IOP. Second, the study design involved the
matching of preexisting glaucoma between cases and con-
trols to decrease the possibility of preexisting glaucoma con-
founding our results, such as an increased baseline likelihood
for glaucoma surgery between groups. Third, restricting the
study to only patients who received intravitreal bevacizumab
injections for the indication of exudative AMD was important
because central retinal vein occlusion, a separate condition
associated with glaucoma, may also be treated by intravitre-
ous bevacizumab injections. Finally, the study demonstrates
that a greater frequency and a greater total number of bevaci-
zumab injections (eTable in the Supplement) are both associ-
ated with an increased risk for glaucoma surgery; this sup-
ports the robustness of our results.
One limitation of this study is that, although the data-
bases we used are well linked and subject to rigorous quality
control, they did not allow us to access details of individual
disease severity and trajectory, including data such as changes
in IOP and visual field loss. Similarly, making associations with
prescription of glaucoma medications is difficult when pre-
scribing practices are not reliably linked with bona fide
glaucoma diagnoses. Second, this study was unable to
address the issue of compounded vs prepared anti-VEGF
medication because all anti-VEGF medication was com-
pounded bevacizumab. Previous studies have shown the
differences in protein concentration, aggregation, and par-
ticulate matter between compounded and prepared anti-
VEGF medication.37,38 Finally, it is important to appreciate that,
in general, causation cannot be conclusively established in
case-control studies.
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 Repeated Bevacizumab Injections and Risk for Glaucoma Surgery Original Investigation Research

this sustained IOP elevation may lead to a greater need for

Conclusions
The results of this study are consistent with those of previ-
ous studies suggesting that repeated intravitreous injections
of anti-VEGF medications can lead to a sustained increase in
IOP. Our study expands on those studies by showing that
surgical intervention for glaucoma. This risk appears to be
evident for patients who have received 7 or more intravitre-
ous bevacizumab injections per year. Clinicians should be
aware of the potential association of repeated, recent intra-
vitreous anti-VEGF injections for diseases, such as exudative
AMD, with subsequent need for glaucoma surgery.

ARTICLE INFORMATION
Accepted for Publication: December 12, 2016.
Published Online: March 16, 2017.
doi:10.1001/jamaophthalmol.2017.0059
Author Contributions: Dr Etminan had full access
to all the data in the study and takes responsibility
for the integrity of the data and the accuracy of the
data analysis.
Study concept and design: Eadie, Carleton,
Maberley, Mikelberg.
Acquisition, analysis, or interpretation of data:
Eadie, Etminan, Carleton.
Drafting of the manuscript: Eadie, Maberley,
Mikelberg.
Critical revision of the manuscript for important
intellectual content: Eadie, Etminan, Carleton,
Mikelberg.
Administrative, technical, or material support: Eadie,
Maberley.
Study supervision: Etminan, Maberley, Mikelberg.
Conflict of Interest Disclosures: All authors have
completed and submitted the ICMJE Form for
Disclosure of Potential Conflicts of Interest. Dr
Etminan was a paid consultant in Mirena Propecia
litigations. No other disclosures were reported.
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Invited Commentary

Anti-VEGF Injections and Glaucoma Surgery

Rajendra S. Apte, MD, PhD; Mae Gordon, PhD; Michael A. Kass, MD

Intravitreous injections of anti–vascular endothelial growth
factor (VEGF) drugs are used commonly to treat retinal dis-
eases, including age-related macular degeneration (AMD),
diabetic retinopathy, and
retinal vein occlusion. Injec-
Related article page 363 tions of any agent into the
vitreous increase the vol-
ume of the eye and cause a temporary rise in intraocular
pressure (IOP). This is usually self-limited and abates in 30
to 60 minutes.
The original studies of the safety and efficacy of intravit-
reous injections of anti-VEGF drugs found little or no overall
effect on IOP. However, a number of case reports subse-
quently linked intravitreous injections to persistent IOP el-
evations, some of which required ocular hypotensive medi-
cation, laser trabeculoplasty, and even glaucoma surgery.1-3
A post hoc analysis of the ANCHOR (Anti-VEGF Antibody for
the Treatment of Predominantly Classic Choroidal Neovascu-
larization of Age-Related Macular Degeneration) and MARINA
(Minimally Classic/Occult Trial of the Anti-VEGF Antibody
Ranibizumab in the Treatment of Neovascular Age-Related
Macular Degeneration) trials found that 11% of eyes treated with
ranibizumab had an IOP of 25 mm Hg or greater compared with
5% of control eyes.4 Similarly, a post hoc analysis of patients
treated for center-involved diabetic macular edema found sus-
tained IOP elevations or initiation or augmentation of ocular
hypotensive medication in 9.5% of participants treated with
ranibizumab and prompt or delayed laser treatment but in only
3.4% of participants who received sham injection and laser
treatment.5
Intraocular pressure elevation has been reported after in-
travitreous injection of various anti-VEGF agents, including be-
vacizumab, ranibizumab, and aflibercept.6 Some studies have
found that sustained IOP elevations are related to the num-
ber of injections,2,5 while other studies have not confirmed this
association.3
In this issue of JAMA Ophthalmology, Eadie and colleagues7
attempt to clarify this association by using glaucoma surgery as
the study end point. They performed a case-control study of 74
patients who received intravitreous injections of bevacizumab
for AMD and subsequently had glaucoma surgery. Glaucoma
surgery was defined as trabeculectomy, glaucoma drainage
device, or cycloablative procedure. This definition did not in-
clude laser trabeculoplasty, minimally invasive glaucoma sur-
gery, or combined cataract and glaucoma surgery. The authors
used a 10:1 matching for controls, who received injections but
did not undergo glaucoma surgery. They reported that pa-
tients who received 7 or more intravitreous injections per year
had an adjusted rate ratio (RR) of 2.48 (95% CI, 1.25-4.93) for
having glaucoma surgery compared with patients who had 3 or
fewer injections per year. Patients who had 12 or more injec-
tions over the follow-up period had an adjusted RR for glau-
coma surgery of 2.61 (95% CI, 1.14-5.98) compared with pa-
tients who received 6 or fewer injections. It should be
emphasized that 58 cases (78.4%) and 580 controls (78.4%) had
glaucoma at baseline. Thus, it is unclear whether the conclu-
sions of this study can be extrapolated to a more general group
of patients with AMD. For the 16 cases and 160 controls who did
not have glaucoma at baseline, the authors did not separately
report the number of injections given or the follow-up time.
The case-control study of Eadie and colleagues has some
unusual features. First, the authors used a 10:1 match of con-
trols and cases, which is much greater than the 3:1 or 4:1 ratios
that are thought to reach maximum statistical efficiency.8
Second, the cases and controls were matched for duration of
follow-up. Typically, follow-up time is treated as a variable in
the multivariable model. Finally, the authors state that con-
trols were selected and matched for the number of injections
per year. This is unusual because the number of injections per
year is the independent variable in the analysis. In Table 2 of
the article, it appears that cases and controls were not matched
for the number of injections per year. The authors’ hypoth-
esis could have been tested more efficiently by using all
patients who met the inclusion criteria (receiving an intravit-
reous bevacizumab injection in the calendar year and subse-
quently undergoing glaucoma surgery) to allow an estimate of
the effect of age, preexisting glaucoma, exposure time, and
number of injections. It would also be informative to com-
pare a control group who had glaucoma at baseline and who
did not receive anti-VEGF injections to determine the inci-
dence of glaucoma surgery over the same period.
This study demonstrates some of the benefits of big data
analysis. By using patient data from the Provincial Retinal
Diseases Treatment Program in British Columbia and linked

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